Synthesis of (-)-Deoxypukalide, the Enantiomer of a DegradationProduct of the Furanocembranolide Pukalide

James A. Marshall* and Elva A. Van Devender

Department of Chemistry, University of Virginia, PO Box 400319, Charlottesville, Virginia 22904

jam5x@virginia.edu

Received August 22, 2001

A convergent stereoselective synthesis of (-)-deoxypukalide is described. This substance has notyet been found in Nature but is obtained through deoxygenation of pukalide, the first naturallyoccurring furanocembrane to be structurally elucidated. The route features a new intraannularfuran synthesis that entails treatment of a 4-oxopropargylic â-keto ester with silica gel. The productof this novel reaction, a 3-carboxy 2,5-bridged furan, is formed in 96% yield. The synthetic strategywas strongly directed by molecular mechanics calculations, which provided valuable insight intostereodefining steps including double bond stereochemistry and butenolide configuration.

Furanocembranolides are marine natural productsisolated from various soft coral species in tropical andtemperate waters throughout the world.1 These com-pounds have received relatively little attention, in part,because of their limited availability. Studies to dateindicate that certain members of the family exhibit potentneurotoxicity, antiinflammatory, and antifeedant activ-ity.2

The furanocembranolides may be divided into twoclasses: those in which the substituent at the C4 positionis a CH3 and those with a more highly oxidized CHO orCO2Me C4 substituent. Rubifolide3 is a representative ofthe former class, whereas the latter more populated classincludes pukalide,4 acerosolide,5 and lophotoxin.6

The few recorded syntheses of furanocembranolideshave employed two differing solutions to the challengingproblem of constructing the strained furanocyclic struc-ture that typifies these substances. In the first a 2,3,5-trisubstituted furan ring is constructed, the appropriateappendages at C2 and C5 are elaborated, and themacrocycle is closed. This strategy suffers from twoproblems: (1) the relatively sensitive furan moiety isintroduced early in the sequence, which limits the rangeof conditions that can be employed for subsequent steps,and (2) the bond forming step in the cyclization must besufficiently energetic to overcome the unfavorable en-thalpic and entropic factors attending formation of the

strained ring. Paquette and Astles utilized this approachin their synthesis of acerosolide (eq 1).7

An alternative solution to bridged furan formationentails macrocyclization of an intermediate in which thefuran ring is absent but elements of its eventual forma-tion are present. Following cyclization, these elementsare modified to enable intraannular furan formation tobe effected. This approach offers two advantages: (1) the

(1) Marshall, J. A. Recent Res. Dev. Org. Chem. 1997, 1, 1.(2) (a) Wright, A. E.; Burres, N. S.; Schulte, G. K. Tetrahedron Lett.

1989, 3491. (b) Abramson, S. N.; Trischman, J. A.; Tapiolas, F. M.;Harold, E. E.; Fenical, W.; Taylor, P. J. Med. Chem. 1991, 34, 1798.(c) Groebe, D. R.; Dumm, J. M.; Abramson, S. N. J. Bio. Chem. 1994,269, 8885. (d) Hyde, E. G.; Boyer, A.; Tang, P.; Xu, Y.; Abramson, S.N. J. Med. Chem. 1995, 38, 2231. (e) Hyde, E. G.; Thornhill, S. M.;Boyer, A.; Abramson, S. N. J. Med. Chem. 1995, 38, 4704. (f) Look, S.A.; Burch, M. T.; Fenical, W.; Qi-tai, Z.; Clardy, J. J. Org. Chem. 1985,50, 5741. (g) Fenical, W. J. Nat. Prod. 1987, 50, 1001.

(3) Williams, D.; Anderson, R. J.; Van Duyne, G. D.; Clardy, J. J.Org. Chem. 1987, 52, 332.

(4) Missakian, M. G.; Burreson, B. J.; Scheuer, P. J. Tetrahedron1975, 31, 2513.

(5) Chan, W. R.; Tinto, W. F.; Laydoo, R. S.; Manchand, P. S.;Reynolds, W. F.; McLean, S. J. Org. Chem. 1991, 56, 1773.

(6) Fenical, W.; Okuda, R. K.; Bandurraga, M.; Culver, P.; Jacobs,R. S. Science 1981, 212, 1512. (7) Paquette, L. A.; Astles, P. C. J. Org. Chem. 1993, 58, 165.

Figure 1. Representative furanocembranolides.

8037J. Org. Chem. 2001, 66, 8037-8041

10.1021/jo016048s CCC: $20.00 © 2001 American Chemical SocietyPublished on Web 11/03/2001

enthalpic energy cost of macrocyclization is considerablydiminished, and (2) the resonance energy associated withfuran formation partially or fully offsets the resultantincrease in strain-energy. Our previous synthesis ofrubifolide embodied this “furan-last” strategy.8

The target of the present studies is deoxypukalide. Thisfuranocembranolide, not yet found in Nature, can beprepared from pukalide through treatment with Zn andEtOH (eq 3).9 The double bond stereochemistry was

established by Tius using NOE analysis. That the productof this deoxygenation possesses a (Z)-double bond is notsurprising given the probable stepwise nature of thedeoxygenation reaction and the high strain-energy of the(E) isomer (Figure 2).

In our projected synthesis of deoxypukalide we envi-sioned a “furan-last” strategy similar to that employed

for rubifolide (Figure 3). However, we harbored gravemisgivings about the probable success of the furan-forming allenone cyclization step in which the C3 methylsubstituent in C derived from A would be replaced by aCO2Me group in D derived from B. Subsequent elimina-tion of the OR substituent in furans C or D affords thevinylfuran products. Two problems were envisioned inthe ester application: (1) unlike A, the precursor allenoneester B would be highly susceptible to nucleophilic 1,4-addition, and (2) the developing positive charge at theCdO position in B would be destabilized by the electron-withdrawing CO2Me substituent. For these reasons wesought alternative methodology more amenable to thepreparation of 3-carboxy-2,5-disubstituted furans.

A simple solution to this problem was arrived at by“rearranging” the allenone keto ester structure to anR-propargylic â-keto ester G or H (Figure 4). The pres-ence of a leaving group at the 4-position of the propargylicsubstituent, as in G, should favor the SN2′ heterocycliza-tion as illustrated. In fact, Wipf and co-workers haveeffected such a conversion.10 To further facilitate thecyclization process, we introduced a carbonyl substituentas in H for our “leaving group”, thereby profiting fromthe favorable energetics of 1,4-additions and considerablyexpanding the range of conditions that might be em-ployed for the cyclization. Subsequent enolization towardthe furan ring should be favored by conjugation and the(Z) double bond geometry would be favored in consider-ation of the strain noted in Figure 2. The feasibility ofthis approach was demonstrated with simple acyclicâ-keto ester ynones,11 but it remained to be tested in anintramolecular context.

Our projected synthesis of deoxypukalide parallels ourprevious route to rubifolide in which (S)-(-)-perillylalcohol 1 served as the starting material.8 Through thischoice we would arrive at the enantiomer of deoxy-pukalide derived from natural material.4 However, therewas no compelling reason to favor the “natural” isomer,

(8) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1997, 62, 4313.(9) Tius, M. Department of Chemistry, University of Hawaii.

Unpublished results.

(10) Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem. 1998, 63,7132.

(11) Marshall, J. A.; Zou, D. Tetrahedron Lett. 2000, 41, 1347.

Figure 2. Calculated energy differences (Macromodel 5.5)between (E)- and (Z)-deoxypukalide (the enantiomer is de-picted). Note the significant twist angle a/b/c/d of the vinyl-furan moiety in the (E) isomer.

Figure 3. Possible strategies for the synthesis of 2,3,5-trisubstituted furans related to furanocembranolides.

Figure 4. Alternative strategy for the synthesis of 3-carboxy-2,5-disubstituted furans.

8038 J. Org. Chem., Vol. 66, No. 24, 2001 Marshall and Van Devender

so the choice was made on a purely economic basis.12 Thestarting sequence, depicted in Scheme 1, is an improvedversion of our previous route to the alkynyl acetal 6 inwhich the Ohira methodology13 for alkynylation (4 f 6)replaces the previous Corey-Fuchs methodology.14 Ad-dition of the lithioalkyne 7 to aldehyde 8 followed byprotecting group adjustments afforded alcohol 11 in highoverall yield.

The derived aldehyde 12 was converted to alcohol 14through addition of the lithio derivative of propargylicether 13 (Scheme 2). Although alcohol 14 and the derivedintermediates 15-20 are most likely mixtures of fourdiastereoisomers, the 1H NMR spectra of these com-pounds were remarkably free of extraneous peaks, sug-gesting that interactions between the various stereo-

centers are relatively modest. Acetal hydrolysis andsubsequent protection of the secondary alcohol 15 led toaldehyde 16. The â-keto ester 18 was efficiently preparedin one step through SnCl2-promoted homologation withtert-butyl diazoacetate (17).15 We initially conducted thisstep with ethyl diazoacetate, which yielded the ethylâ-keto ester. However, this derivative was less robustthan the tert-butyl analogue and a number of thesubsequent steps proceeded in lower yield. We also hadmisgivings about the ultimate conversion of the ethylester to its methyl analogue, although this was not amajor consideration. Methyl diazoacetate, if it werecommercially available, would presumably suffer thesame drawbacks encountered with the ethyl ester. As willbe seen, the tert-butyl ester proved highly satisfactory.

Ensuing selective cleavage of the PMB ether 18 withDDQ at pH 7 and subsequent iodide formation yieldedthe macrocyclization precursor, â-keto ester 20. Thecyclization was effected (Scheme 3) in 83% yield upontreatment of 20 with 0.9 equiv of KO-t-Bu in THF at -78°C at moderately high dilution (0.005 M). The TBS etherin the resulting cyclic ynone 21 was slowly, but selec-tively, cleaved to alcohol 22 by treatment with PPTS inEtOH at room temperature over a period of 10 days.Increasing the temperature of this reaction led to con-siderable byproduct formation at the expense of 22.

Exposure of the Dess-Martin oxidation16 product,ynone 23, to silica gel in hexanes gave the carboxy furan24 in 96% yield for the two steps! As already stated,molecular mechanics calculations17 clearly showed thata cis double bond at the 7,8-position, as in 26, would behighly favored over the corresponding trans isomer (seeFigure 2). Treatment of ketone 24 with the Cominspyridyl triflimide reagent 2518 yielded a 1:1 mixture ofdiastereomeric enol triflates 26, which afforded a com-

(12) Current prices for (R)- and (S)-perillyl alcohol from the 2000-2001 Aldrich catalogue are $33.60/g and $1.59/g.

(13) Ohira, S. Synth. Commun. 1989, 19, 561.(14) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.

(15) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258.(16) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. We

prepared the Dess-Martin periodinane reagent used in this study froma modified procedure that utilizes oxone: Frigerio, M.; Santagostino,M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.

Scheme 1

Scheme 2

Scheme 3

Synthesis of (-)-Deoxypukalide J. Org. Chem., Vol. 66, No. 24, 2001 8039

parable mixture of methylated products 27 in high yieldthrough Pd-catalyzed coupling with Me2Zn. Cleavage ofthe propargylic DPS ether 27 with TBAF and Dess-Martin periodinane oxidation of the propargylic alcohol28 afforded ketone 29 as a single stereoisomer. Thestereochemistry of the double bond was confirmed byNOE studies.

Installation of the embedded butenolide moiety waseffected along the lines previously employed in ourrubifolide synthesis.8 Thus reduction of ketone 29 withK-Selectride gave rise to propargylic alcohol cis-28, as asingle diastereomer (Scheme 4). The basis for thisselectivity can be seen in the calculated structure, shownin Figure 5, in which the C8 substituent adopts a nearlyperfect Felkin-Anh orientation19 with respect to the C10carbonyl.

Conversion of alcohol 28 to the trifluoroacetate 30 andin situ Pd-catalyzed carbohydroxylation yielded the al-lenoic acid 31, which without purification was stirredwith 10% AgNO3 on silica gel in hexanes to afford thebutenolide 32 in 58% yield for the three steps. At thispoint our choice of a tert-butyl ester proved remarkablyprescient. Pyrolysis in a sealed glass tube at 210 °C for20 min followed by treatment of the acid pyrolysate 33with TMSCHN2 afforded crystalline deoxypukalide 34 in92% yield. The relative stereochemistry of this interme-diate was confirmed through single-crystal X-ray struc-ture analysis. Unfortunately, we have been unable tosecure spectral data for the authentic material as the

degradation studies were never published and the origi-nal spectra have been either discarded or misplaced.9

A slight variation on the route to butenolide startingfrom the 1:1 mixture of diastereomeric propargylic alco-hols 35 was also pursued (Figure 7). These alcohols weresynthesized by a route parallel to that described for thetert-butyl ester 28 starting from the â-keto ethyl esteranalogue of 18, mentioned previously.20 The lower yieldin several of the steps in the ethyl ester route precipitatedour switch to the more efficent tert-butyl route. Theimpetus for the study came from molecular mechanics

(17) The program Macromodel 5.5 was employed for these calcula-tions. Global minimum multiple conformer searching was achievedwith the Monte Carlo option in CSRCH (Conformer Search) employingthe MM2 force field in conjunction with the Truncated NewtonConjugate Gradient (TNCG) minimization protocal through multiplestep interations (typically 1000 or more) until the minimum energyconformer was found multiple times. For a description of the program,see: (a) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J.Comput. Chem. 1990, 11, 440. (b) Chang, G.; Guida, W. C.; Still, W.C. J. Am. Chem. Soc. 1989, 111, 4379.

(18) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 6299.(19) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1971,

379. Anh, N. T. Top. Curr. Chem. 1980, 88, 145.(20) The synthesis of this is described in: Van Devender, E. A. Ph.D.

Dissertation, University of Virginia, 2002.

Scheme 4

Figure 5. Conformational basis for the stereoselective reduc-tion of ynone 29. The methyl ester was employed for thecalculations.

Figure 6. Calculated energies (Macromodel 5.5) of diastere-omeric allenic acids.

Figure 7. Equilibration of the intermediate allenylpalladiumstereoisomers derived from trifluoroacetates 36.

8040 J. Org. Chem., Vol. 66, No. 24, 2001 Marshall and Van Devender

calculations,17 which showed that allenic acid 40 wasfavored by more than 1 kcal/mol over the diastereomer(Figure 6). We assumed that the allenylpalladium pre-cursor 38 to this acid would be similarly favored over 37.Acid 40 is the precursor of butenolide 39. Our previousstudies indicated that conversion of enantioenrichedpropargylic mesylates to allenic esters through Pd-catalyzed carbomethoxylation proceeds with varyingamounts of racemization.21 The percent racemizationincreased with the mol % of catalyst in keeping with theknown behavior of chiral allenylpalladium intermedi-ates.22 We also noted that allenic esters could be racem-ized by treatment with Ph3P, the ligands employed inthe carbonylation chemistry. Thus the allenic acid itselfis formed in an isomerizing environment. Accordingly,we felt there was a good chance that allene equilibrationcould be induced and the result would favor the requisitebutenolide precursor. In fact when the three-step acyla-tion, carbonylation, and allenic acid cyclization sequencewas performed on the 1:1 mixture of alcohols 35 (trans-35 and cis-35 in Figure 7) with a full equivalent of Pdcatalyst, butenolide 39 was obtained as the sole product.Furthermore, when the pure alcohol cis-35 was subjectedto the three-step sequence with a full equivalent ofcatalyst, butenolide 39 was again exclusively formed.These results strongly suggest that equilibration of thetransient allenylpalladium intermediates 37 and 38 leadsto a predominance of 38, as surmised from our calcula-tions. However, the yields of these reactions were in the20-30% range. Thus it is possible that small amountsof a minor isomer could have escaped detection. It is alsopossible that a minor isomer, if present, could have

undergone decomposition during the course of the equili-bration. Despite repeated efforts, we were unable toseparate the mixture of cis and trans alcohols 35 tosecure a sample of pure trans isomer for a more rigoroustest of the equilibration hypothesis. Given the low ef-ficiency of the equilibration sequence, we did not pursuethe matter further.

The foregoing synthesis of (-)-deoxypukalide is notablefor its efficiency and high degree of stereocontrol, despitethe use of nonselective reactions that led to intermediatesconsisting of up to eight diastereomers. The ultimatesuccess of the route can be attributed to favorableconformational and steric factors that facilitated highlycontrolled introduction of the key C10 stereocenter andthe C7 double bond.

Acknowledgment. We thank Dr. Michal Sabat forhis heroic efforts in solving the difficult X-ray structureof our synthetic ent-deoxypukalide. This research wassupported by Grant R01-GM29475 from the NationalInstitute for General Medical Sciences and a grant fromthe National Science Foundation (CHE-9901319). Wegratefully acknowledge the NIH for 20 continuous yearsof support for our research on cembrane and cembra-nolide synthesis. The synthesis reported in this articlemarks the termination of this project. We also acknowl-edge the kind cooperation of Marcus Tius for permissionto cite his unpublished findings on the structure ofdeoxypukalide.

Supporting Information Available: Complete experi-mental details for the preparation of all intermediates in thesequence leading to ent-deoxypukalide, selected 1H NMRspectra, and an ORTEP diagram and structure parametersfor synthetic ent-deoxypukalide 34. This material is availablefree of charge via the Internet at http://pubs.acs.org.

JO016048S

(21) Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997,62, 367.

(22) Racemization of allenyl/propargyl palladium intermediates hasbeen studied previously. See ref 21 and (a) Elsevier, C. J.; Mooiweer,H. H.; Kleijn, H.; Vermeer, P. Tetrahedron Lett. 1984, 5571. (b)Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1985, 50, 3042. (c) Elsevier,C. J.; Kleijn, H.; Boersma, J.; Vermeer, P. Organometallics 1986, 5,716.

Synthesis of (-)-Deoxypukalide J. Org. Chem., Vol. 66, No. 24, 2001 8041